更新于：2024-11-01

GLP-2

更新于：2024-11-01

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100 项与 GLP-2 相关的临床结果

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100 项与 GLP-2 相关的转化医学

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0 项与 GLP-2 相关的专利（医药）

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1,027

项与 GLP-2 相关的文献（医药）

2024-12-01·Cellular and Molecular Life Sciences

Role of the GLP2–Wnt1 axis in silicon-rich alkaline mineral water maintaining intestinal epithelium regeneration in piglets under early-life stress

Article

作者: Dai, Xue-Yan ; Xu, Ya-Ru ; Li, Jin-Long ; Zhao, Bi-Chen ; Chen, Jian ; Xu, Xiang-Wen ; Kang, Jian-Xun

AbstractStress-induced intestinal epithelial injury (IEI) and a delay in repair in infancy are predisposing factors for refractory gut diseases in adulthood, such as irritable bowel syndrome (IBS). Hence, it is necessary to develop appropriate mitigation methods for mammals when experiencing early-life stress (ELS). Weaning, as we all know, is a vital procedure that all mammalian newborns, including humans, must go through. Maternal separation (MS) stress in infancy (regarded as weaning stress in animal science) is a commonly used ELS paradigm. Drinking silicon-rich alkaline mineral water (AMW) has a therapeutic effect on enteric disease, but the specific mechanisms involved have not been reported. Herein, we discover the molecular mechanism by which silicon-rich AMW repairs ELS-induced IEI by maintaining intestinal stem cell (ISC) proliferation and differentiation through the glucagon-like peptide (GLP)2–Wnt1 axis. Mechanistic study showed that silicon-rich AMW activates GLP2-dependent Wnt1/β-catenin pathway, and drives ISC proliferation and differentiation by stimulating Lgr5+ ISC cell cycle passage through the G1–S-phase checkpoint, thereby maintaining intestinal epithelial regeneration and IEI repair. Using GLP2 antagonists (GLP23−33) and small interfering RNA (SiWnt1) in vitro, we found that the GLP2–Wnt1 axis is the target of silicon-rich AMW to promote intestinal epithelium regeneration. Therefore, silicon-rich AMW maintains intestinal epithelium regeneration through the GLP2–Wnt1 axis in piglets under ELS. Our research contributes to understanding the mechanism of silicon-rich AMW promoting gut epithelial regeneration and provides a new strategy for the alleviation of ELS-induced IEI.

2024-12-01·Molecular Biology Reports

Insights into the structure and activation mechanism of some class B1 GPCR family members

Review

作者: Aksu, Hayrunisa ; Uba, Abdullahi Ibrahim ; Demirbilek, Ayşenur

In humans, 15 genes encode the class B1 family of GPCRs, which are polypeptide hormone receptors characterized by having a large N-terminal extracellular domain (ECD) and receive signals from outside the cell to activate cellular response. For example, the insulinotropic polypeptide (GIP) stimulates the glucose-dependent insulinotropic polypeptide receptor (GIPR), while the glucagon receptor (GCGR) responds to glucagon by increasing blood glucose levels and promoting the breakdown of liver glycogen to induce the production of insulin. The glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) elicit a response from glucagon-like peptide receptor types 1 and 2 (GLP1R and GLP2R), respectively. Since these receptors are implicated in the pathogenesis of diabetes, studying their activation is crucial for the development of effective therapies for the condition. With more structural information being revealed by experimental methods such as X-ray crystallography, cryo-EM, and NMR, the activation mechanism of class B1 GPCRs becomes unraveled. The available crystal and cryo-EM structures reveal that class B1 GPCRs follow a two-step model for peptide binding and receptor activation. The regions close to the C-termini of hormones interact with the N-terminal ECD of the receptor while the regions close to the N-terminus of the peptide interact with the TM domain and transmit signals. This review highlights the structural details of class B1 GPCRs and their conformational changes following activation. The roles of MD simulation in characterizing those conformational changes are briefly discussed, providing insights into the potential structural exploration for future ligand designs.

2024-11-01·Journal of Equine Veterinary Science

Studies in vitro of equine intestinal glucagon-like peptide-2 secretion

Article

作者: Fitzgerald, D M ; Sibthorpe, P E M ; Sillence, M N ; de Laat, M A

Equine insulin dysregulation (ID) is a significant metabolic problem because the hyperinsulinaemia that develops increases the animal's risk of developing laminitis, a debilitating foot condition. The role of gastrointestinal factors, such as incretin hormones, in the pathogenesis of ID and hyperinsulinaemia in horses is poorly understood, particularly in comparison to other species. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic peptide released from L cells in the gastrointestinal tract and is implicated in metabolic dysfunction in other species. The aim of this study in vitro was to establish basic physiological understanding about intestinal secretion of GLP-2 in horses. Basal and glucose-stimulated GLP-2 secretion was measured in post-mortem tissue samples from the duodenum, jejunum, and ileum. We observed that GLP-2 secretion was minimal in samples from the duodenum compared to the jejunum and ileum (5-9-fold higher; P < 0.05). Furthermore, GLP-2 secretion was not responsive to glucose stimulation in the ileum or duodenum but was responsive to glucose in the jejunum. This effect in the jejunum was inhibited by 30 % (P = 0.02) using phlorizin, a selective sodium-glucose cotransporter-1 (SGLT-1) inhibitor, and by 38 % (P = 0.04) using phloretin, a non-selective SGLT-1/GLUT-2 inhibitor. The localisation of glucose-responsive GLP-2 secretion in the jejunum might be relevant to the development of post-prandial hyperinsulinaemia. This study has provided data on GLP-2 secretion from the equine small intestine that will enable more complex and dynamic studies on the pathogenesis of ID.

105

项与 GLP-2 相关的新闻（医药）

2024-10-17

·GlobeNewswire-Health Care

Rani Therapeutics Announces New Preclinical Pharmacokinetic Data Supporting Transenteric Delivery of GLP-1 Incretin Triagonist

-Transenteric delivery of incretin triagonist GLP-1, GIP, glucagon receptors mimicking the RaniPill route of administration elicits rapid weight loss and bioavailability comparable to subcutaneous injection - - New pharmacokinetic data provides further evidence of the RaniPill platform’s potential to enable oral delivery of multiple obesity treatments - - Phase 1 study for RT-114, an oral GLP-1/GLP-2 dual agonist for the treatment of obesity, expected to initiate in 2025 - SAN JOSE, Calif., Oct. 17, 2024 (GLOBE NEWSWIRE) -- Rani Therapeutics Holdings, Inc. (“Rani Therapeutics” or “Rani”) (Nasdaq: RANI), a clinical-stage biotherapeutics company focused on the oral delivery of biologics and drugs, today announced new pharmacokinetic data from a preclinical study evaluating a GLP-1, GIP and glucagon receptors incretin triagonist with a delivery method mimicking the RaniPill route of administration. A previous study with this incretin triagonist delivered transenterically demonstrated pharmacodynamic effects comparable to subcutaneous injection. Rani also previously completed a study demonstrating oral delivery of GLP-1 receptor agonist with high bioavailability via the RaniPill capsule. “The pharmacokinetic data announced today combined with the previously announced pharmacodynamic data further highlight the RaniPill’s potential to serve as a novel delivery platform for incretin triagonists, a next generation modality for the treatment of obesity,” said Talat Imran, Chief Executive Officer of Rani Therapeutics. “Overall, the totality of RaniPill preclinical data presented to date is promising and provides scientific validation for the potential of the RaniPill to replace painful injections with oral alternatives with differentiated dosing flexibility for multiple obesity drug candidates. Looking ahead, we are focused on execution of a Phase 1 clinical trial for RT-114, a RaniPill capsule containing ProGen’s GLP-1 / GLP-2 dual-agonist, PG-102, and we are evaluating options to move forward with one or more additional molecules in the obesity space.” Data Highlights The preclinical study evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of an incretin triagonist (GLP-1, GIP, glucagon receptors) when delivered via an endoscope-guided transenteric administration to mimic the RaniPill route of administration, versus the traditional administration route of subcutaneous (SC) injection. The study was conducted in canines separated into two groups. In Group 1 (N=3), 0.12 mg/kg of drug was administered via transenteric delivery by endoscope. In Group 2 (N=5), 0.12 mg/kg of drug was administered by SC injection. Blood samples were collected over 2 weeks for analysis of serum drug concentrations and various PD and safety biomarkers. A single dose of drug delivered via either transenteric or SC routes elicited rapid decreases in body weight and serum lipids. Weight loss observed following transenteric delivery was 9.7 ± 2.5 % versus 6.9 ± 2.1 % following SC injection and is believed to be due to early satiety leading to reduced caloric intake. Additionally, the bioavailability of drug delivered via the transenteric route was comparable to that of drug delivered via the SC route at the same dose. The drug was well tolerated in both groups with no serious adverse events (SAEs) observed or changes in safety markers examined. Transenteric delivery via the RaniPill yielded 80% relative bioavailability versus SC and differences between PK parameters (AUC, Cmax, Tmax) were not statistically significant. AUC (nmol*h/L)Cmax (nmol/L)Tmax (h)Transenteric26963.3 ± 5520.0334.3 ± 32.816.7 ± 10.4SC33509.5 ± 1576.1311.5 ± 26.124 ± 0.0 About Rani Therapeutics Rani Therapeutics is a clinical-stage biotherapeutics company focused on advancing technologies to enable the development of orally administered biologics and drugs. Rani has developed the RaniPill® capsule, which is a novel, proprietary and patented platform technology, intended to replace subcutaneous injection or intravenous infusion of biologics and drugs with oral dosing. Rani has successfully conducted several preclinical and clinical studies to evaluate safety, tolerability and bioavailability using RaniPill® capsule technology. For more information, visit ranitherapeutics.com. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the potential opportunity for the RaniPill platform to enable oral delivery of multiple obesity drug products, the potential for the transenteric delivery via endoscope of an incretin triagonist to mimic the RaniPill route of delivery, the expected initiation of a Phase 1 trial of RT-114 in 2025, the potential for the RaniPill to serve as a novel delivery platform for incretin triagonists, the likelihood that weight loss in the preclinical study of the incretin triagonist was caused by early satiety leading to reduced caloric intake, the belief that the preclinical data are reflective of the potential contributions the RaniPill capsule can make to the GLP-1 receptor agonist space and the broader obesity market, and the potential for Rani to use the RaniPill platform to replace painful injections with oral alternatives with differentiated dosing flexibility for multiple obesity drug candidates. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “believed,” “potential,” “expected,” “looking ahead,” “intended” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Rani’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Rani’s business in general and the other risks described in Rani’s filings with the Securities and Exchange Commission, including Rani’s annual report on Form 10-K for the year ended December 31, 2023, and subsequent filings and reports by Rani. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Rani undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. TrademarksTrade names, trademarks and service marks of other companies appearing in this press release are the property of their respective owners. Solely for convenience, the trademarks and trade names referred to in this press release appear without the ® and ™ symbols, but those references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights, or the right of the applicable licensor to these trademarks and tradenames. Investor Contact:investors@ranitherapeutics.com Media Contact:media@ranitherapeutics.com Charts accompanying this announcement are available at https://www.globenewswire.com/NewsRoom/AttachmentNg/cd69bfb8-05d6-4457-b231-74fbae7b6537 https://www.globenewswire.com/NewsRoom/AttachmentNg/4dc9ac35-87a7-48d7-a985-335cbeb40650

临床1期临床结果

2024-10-14

·生物制药小编

GCGR激动剂被二拒

减肥药概念股Zealand公司再次受挫，推出的用以治疗儿童先天性高胰岛素血症(CHI)的上市申请的新药Dasiglucagon再次遭到了FDA拒绝。去年12月，因为发现第三方合同制造工厂缺陷，Dasiglucagon首次被FDA拒之门外。 Zealand指出，Dasiglucagon二次被拒主要原因在于，FDA对第三方生产工厂的复检没能完成，导致审批进程搁置，FDA并没有提出对dasiglucagon有效性或安全性的担忧。 Dasiglucagon是一种胰高血糖素受体（GCGR）激动剂，其作用是使肝脏将储存的糖原释放到血液中。低血糖是糖尿病最常见的急性并发症之一，患者在有能力持续监测血糖的情况下也并不能完全预防严重低血糖事件。与未发生严重低血糖的患者相比，发生严重低血糖的2型糖尿病患者心力衰竭以及动脉粥样硬化性心血管疾病的风险增加，全因死亡率和短暂性脑缺血发作风险均增加。此外，反复发作的低血糖可能加剧患者的脑缺血性损伤，影响患者免疫反应等。 2021年，Dasiglucagon获得FDA批准上市，用于治疗6岁及以上糖尿病患者的严重低血糖。2022年6月，Zealand与诺和诺德就Dasiglucagon全球许可和开发协议，总交易额为4575万美元，Dasiglucagon将该药的全球商业化交给了后者负责。 Zealand成立于1998年，公司与另一家诺和诺德在地理位置上只隔几英里，Zealand的 CEO在内的多位管理层也曾有在诺和诺德工作的经历。 2010年和2017年，Zealand分别在在丹麦哥本哈根交易所上市以及美国纳斯达克交易所和上市。 Zealand最初也是做降糖，Zealand推出的首个上市产品——利西拉来就是一款GLP-1受体激动剂，不过在2003年便授权给了赛诺菲。近年来因为减肥药的大火，加上之后推出的Dasiglucagon销售业绩表现不佳，Zealand也转变了研发方向，专注于减重药的开发。可以说，这个战略转变对于Zealand的起死回生十分关键，受到减重药利好临床数据的拉动，公司近一年股价上涨了158%。 Zealand围绕减重布局了多款管线，其中最快的Survodutide已经推进到Ⅲ期临床阶段，Survodutide是一种GCGR/GLP-1R双靶点激动剂，与勃林格殷格合作开发，适应症包括减重和MASH。 Zealand还开发了全球首款GLP-1/GLP-2双重激动剂Dapiglutide，目前已经推进到临床Ⅱ期阶段。上个月，Zealand公布了dapiglutide用于减重的II期临床数据，13周时，Dapiglutide组最高减重6.2%，而安慰剂组体重增加了2.1%。还有两款减重管线——一种胰淀素类似物Petrelintide、以及一款GIP受体激动剂ZP6590。因为Dasiglucagon卖的不行，本来Zealand也是缺钱的，去年公司还与一家欧洲投资银行签署了一项9000万欧元的贷款融资协议。今年公司财务状况明显好转，在股票市场的正向表现令公司今年6月通过增发募资了70亿丹麦克朗（约合10亿美元），解下了资金燃眉之急。去年底，Zealand还向FDA递交另外一款新药的上市申请——glepaglutide，一种长效胰高血糖素样肽-2（GLP-2）类似物，用于治疗依赖肠外营养支持的成人短肠综合征患者。参考出处： Zealand's hypoglycemia drug suffers another FDA rejection tied to CDMO inspection | Fierce Pharma FDA knocks back Zealand's dasiglucagon once again | pharmaphorum

临床2期临床3期申请上市

2024-09-24

·生物制品圈

GLP-1领域三位开创者，为何他们能获2024年拉斯克奖？

导读 9月19日，拉斯克基金会将2024年拉斯克临床医学研究奖（Lasker~DeBakey Clinical Medical Research Award）授予马萨诸塞州总医院的乔尔·哈伯纳（Joel Habener）、洛克菲勒大学的斯韦特兰娜·莫约索娃（Svetlana Mojsov）和诺和诺德公司的洛特·比耶雷·克努森（Lotte Bjerre Knudsen），以表彰他们在胰高血糖素样肽-1（GLP-1）受体激动剂及其对肥胖症的应用方面的开创性工作。这一荣誉突显了3位科学家所做出的革命性工作，正是这些工作让我们发现了有生之年最令人兴奋的药物之一。 01 发现GLP-1的历程 20世纪80年代初，乔尔·哈伯纳及其团队利用从鲟鱼胰岛细胞生成的文库，成功分离出编码原胰高血糖素的cDNA。这一发现随后被大鼠原胰高血糖素cDNA序列的鉴定所证实。大约在同一时期，芝加哥大学的格雷姆·贝尔（Graeme Bell）也鉴定了仓鼠、奶牛和人类中的原胰高血糖素cDNA和基因。哺乳动物和鱼类的序列均显示，除了胰高血糖素外，cDNA中还包含与胰高血糖素相关的序列，这些序列类似于20世纪70年代发现的另一种肠道衍生激素，即促胰岛素分泌的葡萄糖依赖性促胰岛素多肽（GIP）。图一 GLP-1的产生机制及其有益作用。胰高血糖素从肠细胞中释放出来，并被加工成其成分，其中之一是GLP-1。GLP-1与胰腺中的受体结合，导致胰岛素分泌。GLP-1 通过与其他组织中的GLP-1受体结合或间接减少炎症而发挥额外的有益作用。图中还包括FDA批准的GLP-1RA 药物列表。贝尔的研究表明，哺乳动物的原胰高血糖素包含两个GLP区域，分别称为GLP-1和GLP-2（图1），其中GLP-1在哺乳动物中高度保守。这些早期研究表明，胰高血糖素和GLPs与胰岛素和甲状旁腺激素类似，都是作为较大的前体激素产生的，并在翻译后裂解成最终的肽类。后来人们发现了特定的内肽酶——前体激素转化酶，这些酶在含有氨基酸精氨酸和赖氨酸的基本位点上裂解前体激素。 1984年夏，丹尼尔·德鲁克（Daniel Drucker）作为博士后研究员加入了哈伯纳实验室，并进行了开创性的研究，描述了预测的原胰高血糖素产物及其生物活性。他将原胰高血糖素cDNA转染到胰岛细胞、垂体细胞和成纤维细胞中。虽然成纤维细胞中的加工过程很少，但他证明GLP-1的生物活性形式在单个碱性位点处被氨基截断，且GLP-1和GLP-2均在转染的垂体和胰岛细胞中进行了加工。在多伦多建立自己的实验室后，德鲁克继续揭示GLP-1和GLP-2的生理作用以及原胰高血糖素表达和加工的分子控制。他的研究表明，肠道原胰高血糖素cDNA与胰腺中表达的形式相同。然而，进一步研究还表明，肠道提取物中的免疫反应性GLP-1肽仅由较小的肽组成，这表明肠道中的加工过程与胰腺不同，且将原胰高血糖素加工成较小肽的效率更高。这一发现与这些肽的促分泌素性质一致，因为口服营养素会刺激它们在肠道中的产生，而不是在胰腺中产生（图1）。德鲁克还确定了GLP-2作为一种肠道生长因子，因为其给药与保护肠道粘膜细胞免受损伤相关。研究表明，GLP-2能增加营养物质的吸收。因此，一种抗降解的GLP-2类似物（在德鲁克实验室研发，后来被指定为替度鲁肽，即teduglutide，于2012年获得美国FDA批准，用于依赖肠外营养治疗的短肠综合征患者的慢性治疗。在这些研究进行的同时，丹麦的延斯·霍尔斯特（Jens Holst）研究了胃手术后餐后反应性低血糖中调节胰岛素分泌的信号。他的研究小组专注于产生胰高血糖素的肠道细胞，而他的实验室工作导致了前体激素分子胰高血糖素原和氧抑胃肽的发现。这些分子包含完整的胰高血糖素氨基酸，但与原胰高血糖素不同，它们缺乏GLP序列。因此，霍尔斯特及其同事将研究重点转向开发免疫测定法，并证明原胰高血糖素在肠道（而非胰腺）中被裂解以产生两种GLP（图1）。他们还证明，从肠道中分离出的原胰高血糖素截断形式（aa 78–108）可以诱导胰岛素产生。上世纪90年代，霍尔斯特的研究小组还表明，输注相同截断形式的原胰高血糖素会导致人体胰岛素分泌并抑制胰高血糖素产生。霍尔斯特研究小组及其他研究小组的进一步工作表明，GLP-1可以抑制胃动力和胃及胰腺的外分泌功能，并抑制食欲和食物摄入量。这些后期研究最终助力了GLP-1激动剂在肥胖症治疗中的应用。 02 GLP-1生物活性形式的发现当哈伯纳实验室正在研究原胰高血糖素时，斯韦特兰娜·莫伊索夫（Svetlana Mojsov）则独立地专注于GLP-1生物活性形式的化学鉴定。莫伊索夫出生于塞尔维亚（当时称为南斯拉夫），并在诺贝尔奖得主布鲁斯·梅里菲尔德（Bruce Merrifield）的实验室完成了关于胰高血糖素化学合成的研究生学习。之后，她前往麻省总医院工作，尽管她与乔尔·哈伯纳（Joel Habener）在同一机构，但她对GLP-1的研究是独立进行的。莫伊索夫利用她在化学领域的背景，采取了一种替代且互补的方法来鉴定GLP-1的生物活性形式。研究表明，在大鼠胰岛素瘤细胞中，预测的GLP-1序列（aa 1–37）并未增加环磷酸腺苷（cAMP）的产生。基于她之前在胰高血糖素方面的工作，她假设氨基酸7–37可能构成长期以来一直寻找的促分泌素GLP-1的活性形式。她合成了GLP-1的独特区域，并随后针对这些GLP-1区域生成了兔抗体。大约在这个时期，她开始与德鲁克和哈伯纳合作，并使用她开发的抗体在大鼠肠道中鉴定出GLP-1（aa 7–37）；然而，他们至关重要的实验是证明GLP-1（aa 7–37）具有生物活性。他们的合作研究发现了GLP-1（aa 7–37）肽能够刺激大鼠胰腺胰岛细胞释放胰岛素。此外，他们还与戈登·韦尔（Gordon Weir）合作，证明了GLP-1（aa 7–27）在体外大鼠胰腺模型中增加胰岛素产生的能力。这项开创性的工作于1987年发表在Journal of Clinical Investigation上。 03 GLP-1在人类中应用的初步研究 1992年，第一项关于GLP-1在人类中的研究展开，该研究证明，输注GLP-1（aa 7–37）肽可诱导胰岛素分泌，并对糖尿病患者及非糖尿病患者均具有抗糖尿病作用。一年后，瑙克（Nauck）及其同事表明，输注GLP-1肽可使2型糖尿病患者的血糖水平恢复正常。然而，随后对GLP-1进行皮下注射的研究却令人失望，因为GLP-1被二肽基肽酶-4（DDP4）酶迅速降解，DDP4抑制剂能够减少GLP-1的降解，并显著增加循环胰岛素水平。DDP4抑制剂，也被称为格列汀类药物，如西格列汀、沙格列汀、利格列汀和阿格列汀等，随后在21世纪中期获得美国FDA批准，用于治疗成人2型糖尿病。霍尔斯特的研究小组也在人类中进行了平行研究，并表明通过泵输注合成的GLP-1（aa 7–36）酰胺（皮下注射）可改善血浆葡萄糖水平、胰岛素敏感性、糖化血红蛋白（HgA1C）和体重，且副作用极小。这项开创性的人类研究为GLP-1的治疗潜力提供了概念验证，并推动了进一步开发GLP-1激动剂以供临床使用的努力。 04 GLP-1受体激动剂尽管临床研究显示GLP-1能够刺激胰岛素产生，但其较短的半衰期（静脉注射和皮下注射后分别为1.5分钟和1.5小时）限制了其临床应用。首个获批用于临床的GLP-1受体激动剂（GLP-1RA）是艾塞那肽，这是一种DPP4蛋白酶抵抗型激素，基于exendin-4并最初从蜥蜴毒液中分离出来。艾塞那肽最初需要每日给药两次，并于2005年获得批准。随后，另一种每周给药一次的艾塞那肽也获批用于治疗2型糖尿病。为了克服这些药物半衰期短所带来的限制，诺和诺德公司的科学家，包括洛特·比耶雷·克努森（Lotte Bjerre Knudsen），致力于开发更稳定的GLP-1RA。克努森在丹麦技术大学攻读化学工程专业时开始在诺和诺德工作。完成学业后，她加入诺和诺德，并专注于通过结合白蛋白来增加GLP-1RA的半衰期。白蛋白能与多种不溶性底物结合，包括脂肪酸和类固醇，并促进它们在血液中的溶解和运输。克努森的研究小组对GLP-1进行了脂肪酸衍生物处理，生成了能够与白蛋白以可逆方式结合的类似物，从而保护GLP-1免受DPP4降解和肾脏过滤。这些研究促使了利拉鲁肽的发现，这是首个适合每日给药一次的GLP-1类似物。鉴于GLP-1RA通过注射给药，因此更长效的剂型更受欢迎。首个长效GLP-1RA是他司鲁肽，在III期临床试验中显示出良好效果，但由于极少数患者出现过敏反应，因此未提交给FDA批准。诺和诺德公司的克努森研究小组继续专注于白蛋白结合，并通过修饰GLP-1和脂肪酸部分连接子，成功开发了司美鲁肽这一长效GLP-1RA，可每周给药一次。 05 GLP-1R激动剂的其他益处最近令人振奋的研究表明，GLP-1RA的益处远不止于糖尿病和肥胖。在至少8项评估糖尿病患者心血管结局的随机临床试验中，对GLP-1RA进行了研究。其中四项临床试验达到了主要目标，并显示出CV结局的显著降低。值得注意的是，在SUSTAIN-6研究中，市场份额最大的GLP-1RA药物司美鲁肽实现了主要复合终点（首次发生CV相关死亡）的26%减少，以及非致死性心肌梗死或非致死性卒中的减少。另一项SELECT试验显示，在未患糖尿病的肥胖患者中，司美鲁肽治疗与CV死亡、非致死性心肌梗死或非致死性卒中的发生率降低相关。最后，STEP-HFpEF试验表明，在射血分数保留的心力衰竭患者中，司美鲁肽治疗与症状和身体限制的减少、运动功能的更大改善以及更大的体重减轻相关。这些试验共同表明，GLP-1RA治疗可能对心脏具有保护作用，防止其受损。这种保护作用的机制可能是多方面的。当然，这些药物通过抗糖尿病作用减轻体重和控制血糖可能是其心脏保护作用的关键因素。然而，临床前和临床研究表明，这些药物对心脏的有益作用超出了其对体重和糖尿病的影响。例如，在SELECT试验中，司美鲁肽对心脏的有益作用超过了体重减轻的程度。此外，GLP-1RA还被证明可以降低血压和致动脉粥样硬化的脂蛋白水平。最后，现在有证据表明，GLP-1RA治疗与全身性炎症的减少相关，这似乎与体重减轻的程度无关，也可能解释了其CV益处。 GLP-1-RAs在肝病和肾病领域也进行了研究。FLOW试验表明，司美鲁肽可降低糖尿病和慢性肾脏病患者临床上重要的肾脏结局和心血管疾病死亡风险。ESSENCE研究是一项正在进行中的III期临床试验，旨在研究司美鲁肽在代谢功能障碍相关脂肪性肝炎中的作用。GLP-1RA在肝脏和肾脏中的保护机制尚不清楚，但其作用可能通过这些器官内表达GLP-1R的其他细胞实现。这些药物的抗炎作用也可能有助于其益处。 GLP-1RA在神经系统疾病中的作用也在研究中。两项III期临床试验EVOKE和EVOKE Plus将研究口服司美鲁肽（目前尚未获得FDA批准）在认知功能下降患者中的效果。此外，还提出GLP-1RA可能减少成瘾性和精神疾病。然而，在SELECT试验中，精神疾病方面并未发现差异。队列研究和电子健康记录研究表明，司美鲁肽可能与自杀意念的减少有关。最后，一些研究的事后分析表明，GLP-1RA可能与酒精摄入量的减少有关。尽管这些药物在逆转多种主要疾病方面取得了成功，但其使用也伴随着一系列副作用，包括恶心、呕吐、胰腺炎和注射部位反应。其中一些副作用似乎是由于这些药物与大脑中GLP-1R的结合所致。这些药物的另一个主要副作用是肌肉流失，在某些患者中可高达40%，在老年患者中可能更为严重。还有一个令人担忧的问题是，如果停药，体重增加将完全以脂肪的形式出现，导致这些患者净肌肉量减少。 06 总结 GLP-1RAs的发现由多位研究人员共同完成，并引领了糖尿病和减肥治疗的新策略。这些药物不仅具有代谢作用，还显示出对其他器官的益处，使其有可能用于治疗更多疾病。 GLP-1RAs彻底改变了代谢性疾病的治疗方法，该领域的先驱们因其开创性的发现而真正值得认可。原文链接 Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen awarded Lasker prize for pioneering work on GLP-1 https://www-jci-org.libproxy1.nus.edu.sg/articles/view/186225 识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。